Temozolomide, 3-methyl-8-aminocarbonyl-imidazo[5, 1-d]-1,2,3,5-tetrazin-4(3H)-one, is a known antitumor drug; see for example Stevens et al., J. Med. Chem. 1984, 27, 196-201, and Wang et al., J. Chem. Soc., Chem. Commun., 1994, 1687-1688. It has the formula: 
It is described in U.S. Pat. No. 5,260,291 (Lunt et al.) together with compounds of broadly similar activity such as higher alkyl analogs at the 3-position.
The synthesis of I by the process described in J. Med. Chem. 1984, 27, 196-201 can be simply depicted as follows, even though the authors mention that the cycloaddition of the methylisocyanate to the compound of the formula (B) can proceed through two different intermediates: In this process, 5-amino-1H-imidazole-4-carboxamide (A) is converted into 5-diazo-1H-imidazole-4-carboxamide (B), which is then cyclized with methylisocyanate in dichloromethane to provide a high yield of clinical-grade Temozolomide. However, this process requires isolation of the unstable and potentially dangerous 5-diazo-1H-imidazole-4-carboxamide (B). Moreover, methylisocyanate is a difficult reagent to handle and ship, especially on the industrial scale, and indeed is better avoided in industrial manufacture. Furthermore, the cycloaddition of methylisocyanate requires a very long reaction time: Table I in J. Med. Chem. 1984, 27, 196-201, suggests 20 days.
The production of I by the two processes described in J. Chem. Soc., Chem. Commun., 1994, 1687-1688 provides a low overall yield from 5-amino-1H-imidazole-4-carboxamide (A): less than 20% (unoptimized—about 17% through 5-diazo-1H-imidazole-4-carboxamide (B) and about 15% through 5-amino-N1-(ethoxycarbonylmethyl)-1H-imidazole-1,4-dicarboxamide (C)): Moreover, the unstable 5-diazo-1H-imidazole-4-carboxamide (B) still has to be isolated in the branch of this process that uses it as an intermediate.
Clearly, therefore, there is a need for synthetic methods that are more convenient, especially on an industrial scale, and provide good yields of clinical-grade Temozolomide, or improve the preparation or use of intermediates for the aforementioned processes.